New Statistical Algorithms for the Analysis of Mass - FU Berlin, FB MI ...

4.6. BIOLOGICAL APPLICATIONS 101
4.6 Biological Applications
In addition to the clinical application described in the previous sections mass
spectrometry has also emerged as the preferred method for in-depth characterization
of protein components of biological systems. Many studies have
shown that is is possible to gain key insights into the composition, regulation
and function of molecular complexes and pathways. Thus, mass spectrometrybased
proteomics has evolved to a quite powerful hypothesis-generation platform.
This tool in combination with complementary techniques from areas
such as molecular biology or pharmacology provides a framework to gather
more understanding of complex biological processes. This section will briefly
review some recent studies and show the large range of applications.
4.6.1 Characterization of Protein Complexes
Many proteins found in cells or tissue function as components of larger complexes.
These complexes can vary in size dramatically, from just a few small
proteins clustering together to very large assemblies of dozens of proteins,
such as the ribosome. Since the composition of these complexes is highly regulated
in cells (context and time dependent) unraveling the structure becomes
a real challenge. Mass spectrometry-based proteomics can aid in this issue as
described in the examples below.
Discovering a Mitochondrial Protein Complex Structure
By mass spectrometry-based proteomics analysis of mitochondrial BAD-containing
complexes (Danial et al., 2003) discovered an unexpected physical
association between a key apoptotic protein (BAD) and a key glycolytic protein
(glucokinase). This led to new models to explain how cells coordinate
metabolic signals and survival signals.
Discovering a Transcription-Factor Complex
(Ranish et al., 2004) used mass spectrometry-based proteomics to characterize
a previously unknown component of TFIIH (one of the transcription factors
that make up the RNA polymerase II preinitiation complex) that eventually
succeeded in explaining the molecular basis for a human photosensitivity syndrome.
Discovering a Chaperone Complex
In an early study (Washburn et al., 2001) analyzed the CFTR (cystic fibrosis
transmembrane conductance regulator, an ABC transporter-class protein
and chloride ion channel) interactome using mass spectrometry-based proteomics
and identified specific co-chaperones and chaperone folding pathways
that seem to control mutant channel stability, cell-surface expression and function.
Mutations of CFTR leads to cystic fibrosis and congenital absence of
the vas deferens (part of the male anatomy).
4.6.2 Characterization of Protein Pathways
Another very exciting application of mass spectrometry-based proteomics is
the comparative analysis of biological samples of different conditions, such as